Coatings of acrylamide-based copolymers

ABSTRACT

An implantable device including a conjugate formed of an acrylamide-based copolymer and a bioactive agent is provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/206,417,filed Aug. 9, 2011, which is and which is a continuation of applicationSer. No. 11/639,860, filed Dec. 15, 2006, now U.S. Pat. No. 8,017,141,each of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention generally relates to acrylamide-based copolymers forcoating an implantable device such as a drug delivery stent.

DESCRIPTION OF THE BACKGROUND

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels, such as by employing a stent. Stentsare used not only for mechanical intervention but also as vehicles forproviding biological therapy. To effect a controlled delivery of anactive agent in stent medication, the stent can be coated with abiocompatible polymeric coating. The biocompatible polymeric coating canfunction either as a permeable layer or a carrier to allow a controlleddelivery of the agent.

The existing polymeric coating on a stent can have different types oflimitations. For example, some poly(ester amide) based coatings can havepoor mechanical properties so as to compromise coating integrity, andcoating based on hydrophobic polymers can have problems in controllingrelease of a hydrophilic drug.

Therefore, there is a need for new carrier materials for controlleddelivery of an agent.

The polymer and methods of making the polymer disclosed herein addressthe above described problems.

SUMMARY OF THE INVENTION

Poly(HPMA) is a hydrophilic polymer which has been used to conjugate abioactive agents such as drugs, peptides and proteins. This conjugationcan lead to increased circulation time in the bloodstream of thesebioactive agents as well as these agents' uptake by the cellularendoplasm (Ulbrich K., et al., Advance in Experimental Medicine andBiology: Polymer Drugs in the Clinical Stage, 519:125-143 (2003).

Accordingly, provided in this invention is a coating on an implantabledevice, the coating comprising a acrylamide-based copolymer that canconjugate to a bioactive agent. The polymer can have a chosen degree ofhydrophilicity by virtue of the presence of the hydroxy groups on thepolymer backbone. The coating can have a topcoat or a drug matrix thatincludes the acrylamide-based copolymer described herein. In someembodiments, the acrylamide-based copolymer includespoly[N-(2-hydroxypropyl)methacrylamide] (poly(HPMA)).

The bioactive active agent can be conjugated to the acrylamide-basedcopolymer via a labile linker. The bioactive agent can be conjugated tothe polymer by conjugation to functional groups (e.g., hydrophilicgroups) on the copolymer. In some embodiments, the bioactive agent canbe conjugated to the acrylamide-based copolymer via hydrophilic groupson the acrylamide-based copolymer.

The bioactive agents can be any drugs, peptides, proteins, orcombinations thereof. Some examples of the bioactive agent include, butare not limited to, halofuginone, paclitaxel, docetaxel, estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, mometasone, bioactive RGD, CD-34antibody, abciximab (REOPRO), progenitor cell capturing antibody,prohealing drugs, prodrugs thereof, co-drugs thereof, or a combinationthereof.

An implantable device having a coating described herein can be used totreat, prevent, or ameliorate a vascular medical condition. Someexemplary vascular medical conditions include atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, vulnerable plaque, chronic total occlusion,claudication, anastomotic proliferation for vein and artificial grafts,bile duct obstruction, urethra obstruction, tumor obstruction, andcombinations thereof. For example, the implantable device can be plantedwithin a tissue of a human being, e.g., in the blood vessel.

In some embodiments, the present invention provides a method of forminga coating on the implantable device. The method comprises

providing a copolymer that comprises units derived from at least oneacrylamide monomer,

providing a bioactive agent,

forming a conjugate of the bioactive agent and the copolymer, and

forming a coating comprising the conjugate on the implantable device.

DETAILED DESCRIPTION OF THE INVENTION

Poly[N-(2-hydroxypropyl)methacrylamide] (Poly(HPMA)) is a hydrophilicpolymer which has been used to conjugate a bioactive agents such asdrugs, peptides and proteins. This conjugation can lead to increasedcirculation time in the bloodstream of these bioactive agents as well asthese agents' uptake by the cellular endoplasm (Ulbrich K., et al.,Advance in Experimental Medicine and Biology: Polymer Drugs in theClinical Stage, 519:125-143 (2003).

Accordingly, provided in this invention is a coating on an implantabledevice, the coating comprising a acrylamide-based copolymer that canconjugate to a bioactive agent. The polymer can have a chosen degree ofhydrophilicity by virtue of the presence of the hydroxy groups on thepolymer backbone. The coating can have a topcoat or a drug matrix thatincludes the acrylamide-based copolymer described herein. In someembodiments, the acrylamide-based copolymer includes poly(HPMA).

The bioactive active agent can be conjugated to the acrylamide-basedcopolymer via a labile linker. The bioactive agent can be conjugated tothe polymer by conjugation to functional groups (e.g., hydrophilicgroups) on the copolymer. In some embodiments, the bioactive agent canbe conjugated to the acrylamide-based copolymer via hydrophilic groupson the acrylamide-based copolymer.

The bioactive agents can be any drugs, peptides, proteins, orcombinations thereof. Some examples of the bioactive agent include, butare not limited to, halofuginone, paclitaxel, docetaxel, estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, mometasone, bioactive RGD, CD-34antibody, abciximab (REOPRO), progenitor cell capturing antibody,prohealing drugs, prodrugs thereof, co-drugs thereof, or a combinationthereof.

An implantable device having a coating described herein can be used totreat, prevent, or ameliorate a vascular medical condition. Someexemplary vascular medical conditions include atherosclerosis,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, vulnerable plaque, chronic total occlusion,claudication, anastomotic proliferation for vein and artificial grafts,bile duct obstruction, urethra obstruction, tumor obstruction, andcombinations thereof. For example, the implantable device can be plantedwithin a tissue of a human being, e.g., in the blood vessel.

In some embodiments, the present invention provides a method of forminga coating on the implantable device. The method comprises

providing a copolymer that comprises units derived from at least oneacrylamide monomer,

providing a bioactive agent,

forming a conjugate of the bioactive agent and the copolymer, and

forming a coating comprising the conjugate on the implantable device.

Acrylamide-Based Copolymer

The acrylamide-based copolymer can be formed of an acrylamide ormethacrylamide monomer having a hydrophilic group. Preferably, thehydrophilic group is —OH, —SH, —NRH, —COOH, —COO⁻Na⁺, or —COO⁻K⁺.

In some embodiments, the acrylamide monomer forming the acrylamide-basedcopolymer can be an acrylamide or methacrylamide having the structure offormula I:

wherein R₁ is CH₃ or H, and R₂ can be any group having at least onehydroxyl, thiol, amino or carboxyl group. Examples of R₂ can be shortchain hydroxyalkyl groups, a peptide sequence, an alkyl chain, or alinker.

The acrylamide-based copolymer can have different molar ratios ofmonomers. Such molar ratios of monomers can be designated as n and m.These molar ratios can independently range from about 0.01 to about 0.99and the total values of molar ratios n+m=1. Some examples of the molarratios are about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 0.95. Note,molar ratios of the monomers can affect the hydrophobicity of thecopolymer. A higher ratio of hydrophobic monomers can result in a morehydrophobic copolymer, and vice versa. The hydrophobic nature of thecopolymer can influence the release of a drug embedded, admixed,dissolved, or otherwise included in a matrix or coating including thecopolymer.

The acrylamide-based copolymer can be formed by any established methodof polymerization (see, e.g., Polymer Handbook, by Eric A. Grulke,Akihiro Abe, Daniel R. Bloch, and J. Brandrup (Eds), J&W Wiley, 2003).For example, the acrylamide-based copolymer can be formed by standardfree radical copolymerization and controlled radical polymerization suchas ATRP (T. E. Patten and K. Matyjaszewski, Adv. Mater. 10, (1998) pp.901; K. Matyjaszewski and J. Xia, Chem. Rev. 101 (2001) pp. 2921; M.Kamigaito, T. Audo and M. Sawamoto Chem. Rev. 101 (2001) pp. 3689. andRAFT (reversible addition-fragmentation chain transfer) J. Krstina etal., Macromolecules 28 (1995) pp. 5381; G. Moad et al., WO 96/15157(1996); T. P. Le et al., WO 9801478/A1 (1998); J. Chiefari et al.,Macromolecules 31 (1998) pp. 5559 The polymerization or copolymerizationcan be carried out sequentially to yield a block copolymer ofconcurrently to yield a random copolymer, depending on the desiredproperties of the copolymer. A general scheme of forming theacrylamide-based copolymer is shown in Scheme I:

In Scheme I, R₁ and R₂ are defined as those in Formula I. R₃ is CH₃ orH. R₄ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl, orheterocyclic group. R₄ can bear functional groups such as hydroxyl,alkoxy such as methoxy or ethoxy, thiol, carboxyl, NH, or other groups.Some examples of R₄ are CH₃, ethyl, propyl, 2-hydroxyethyl, butyl, ormethoxyethyl. N and m are molar ratios of the two monomers and areindependently from about 0.01 to about 0.99 and the total values ofmolar ratios n+m=1. Some examples of n and m are about 0.05, about 0.1,about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about0.8, about 0.9, or about 0.95. Z can be O or NH.

In some embodiments, the acrylamide monomer is N-(2-hydroxypropyl)methacrylamide (HPMA). HPMA can easily polymerize alone orcopolymerize with other monomers such as acrylamide, acrylate ormethacrylate monomers to form a HPMA copolymer. Therefore, HPMA can beused as a monomer to introduce a chosen degree of hydrophilicity intothe backbone of the acrylamide-based copolymer by forming a copolymer(s)with other monomers. A general scheme forming the HPMA copolymer can beillustrated by the reaction in Scheme II below:

forming a HPMA-based copolymer having the general formula II

In Scheme II and Formula II, n and m are molar ratios of the twomonomers forming the copolymer and can independently range from about0.01 to about 0.99. Some examples of n and m values are about 0.05,about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about0.7, about 0.8, about 0.9, or about 0.95. R₅ and R₆ are independentlyCH₃ and H. R₇ is a straight or branched C1-C12 alkyl, aryl, cycloalkyl,or heterocyclic group. R₇ can bear functional groups such as hydroxyl,alkoxy such as methoxy or ethoxy, thiol, carboxyl, NH, or other groups.Some examples of R₇ are CH₃, ethyl, propyl, 2-hydroxyethyl, butyl, ormethoxyethyl. An example of the HPMA-based copolymer of formula II iswhere R₅ and R₆ are CH₃, and R₇ is methoxyethyl. This polymer ispoly[N-(2-hydroxypropyl)methacrylamide-co-methoxyethyl methacrylate](HPMA-co-MOEMA), which can be a random or block copolymer.

Linkers

Any biocompatible linker can be used to conjugate a bioactive agent tothe hydrophilic group on a monomer forming the poly(HPMA)-based polymeror on the poly(HPMA)-based polymer itself. In some embodiments, thelinker can be any linker having about 40 atoms or less. In someembodiments, the linker can include poly(ethylene glycol) (PEG),poly(alkylene oxide), C1-C12 short chain alkyl, C1-C12 short chaincycloalkyl, C1-C12 aryl, peptide, protein, oligomer of amino acids orcombinations thereof. In some embodiments, the linker is a labilelinker. For example, such labile linker can include, e.g., a peptidesequence such as glycine-phenylalinine-leucine-glycine. Some otherlabile linkers include, but are not limited to, succinic anhydride,glutaric anhydride, dimethyl succinic anhydride, methyl glutaricanhydride, thioesters, disulfide bonds, PLA-, PLGA-, PCL-oligomers andother ester and anhydride linkages.

In some embodiments, the linker can include a vinyl group and canpolymerize with HPMA or other monomers forming a poly(HPMA)-basedcopolymer having pendant linker molecules. The linker includes a freehydrophilic group (e.g., OH) for conjugation to a bioactive agent.Scheme III shows the formation of an example of a linker having PEG anda methacrylate group.

As shown in Scheme III, a linker, such as PEG, a peptide sequence or analkyl chain, can include two functional groups (e.g., a free amine,hydroxyl, thiol, carboxyl), one functional group being reactive and theother one being protected by a protective group such as benzyl group.The reactive group can react with a reactive vinyl group (e.g., acryloylhalide or methacryloyl halide) to form a vinyl group terminated PEG. Theprotective group can subsequently be removed by a process such ashydrogenation (H₂ gas and Pd/C) to yield a free functional group. Thislinker vinyl molecule with a reactive terminal group can readilycopolymerize with other acrylate, methacrylate or acrylamide monomers toform an acrylamide-based copolymer according to Scheme I, above.

Other examples of useable linkers include, but are not limited to, anybiocompatible linker can be used to conjugate a bioactive agent to thehydrophilic group on a monomer forming the poly(HPMA)-based polymer oron the poly(HPMA)-based polymer itself. In some embodiments, the linkercan be any linker having about 40 atoms or less. In some embodiments,the linker can include poly(ethylene glycol) (PEG), poly(alkyleneoxide), C1-C12 short chain alkyl, C1-C12 short chain cycloalkyl, C1-C12aryl, peptide, protein, oligomer of amino acids or combinations thereof.In some embodiments, the linker is a labile linker. For example, suchlabile linkers can include, e.g., a peptide sequence such asglycine-phenylalinine-leucine-glycine. Some other labile linkersinclude, but are not limited to, succinic anhydride, glutaric anhydride,dimethyl succinic anhydride, methyl glutaric anhydride, thioesters,disulfide bonds, PLA-, PLGA-, PCL-oligomers and other ester andanhydride linkages.

Conjugation of Bioactive Agents

Any bioactive agent can be conjugated to the acrylamide-based copolymer.Conjugation can be achieved by binding force of any nature, e.g.,hydrogen bonding, ionic interaction (e.g., ion pairs), interpenetratingnetwork, or covalent chemical bonding. Preferably, the binding forcebetween the bioactive agent and the acrylamide-based copolymer iscovalent chemical bonding.

Conjugation of the bioactive agent to the acrylamide-based copolymer bychemical bonding can be carried out using any established couplingchemistry. For example, where the acrylamide-based copolymer or a linkerattached thereto bears hydrophilic groups such as hydroxyl, amino orcarboxylic groups, coupling the bioactive group and the hydrophilicgroups can be readily achieved using EDC chemistry (see, e.g., OldeDamink L. H., et al., Biomaterials. 17(8):765-73 (1996)). Some otherexamples of coupling the bioactive agent to the hydrophilic groups viachemical bonding are described in U.S. patent application Ser. No.10/857,141, the teaching of which is incorporated hereto in its entiretyby reference.

Coating Construct

The acrylamide-based copolymer described herein can be used with orwithout a bioactive agent conjugated thereto. In some embodiments, theacrylamide-based copolymer can be used as a matrix including a bioactiveagent or a topcoat on an implantable device to control the release ofthe bioactive agent (e.g., a drug) from the implantable device. In someembodiments, the acrylamide-based copolymer can form a topcoat on animplantable device as surface functionalization of the implantabledevice. The acrylamide-based copolymer can include a bioactive agentpermanently bound thereto, the bioactive agent imparting beneficialsurface biological properties to the implantable device. The matrix ortopcoat can further include a biocompatible polymer other than theacrylamide-based copolymer (“biocompatible polymer”) described herein.

Release of the bioactive agent from the matrix or topcoat of theimplantable device can proceed via several mechanisms, which varyaccording to the nature of the binding force between the bioactive agentand the acrylamide-based copolymer. For example, where the binding forcebetween bioactive agent and the acrylamide-based copolymer is notcovalent chemical bonding, the bioactive agent can diffuse out of thematrix or topcoat so as to release into the blood stream or a tissue ofa human being who receives an implantable device having a matrix ortopcoat described herein. Where the nature of binding between abioactive agent and the acrylamide-based copolymer is covalent bondingvia a labile linker, release of the bioactive agent can be achieved bydegradation or disruption of the labile linker to cause the bioactiveagent to release into the blood stream or a tissue of a human being whoreceives an implantable device having a matrix or topcoat describedherein. Degradation or disruption of the labile linker can be achievedby enzymedic degradation or hydrolytic degradation of the labile linker.

Biocompatible Polymers

The acrylamide-based copolymer described herein can be used with otherbiocompatible polymers. The biocompatible polymer can be biodegradable(either bioerodable or bioabsorbable or both) or nondegradable and canbe hydrophilic or hydrophobic. Representative biocompatible polymersinclude, but are not limited to, poly(ester amide),polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalkanaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyphosphazenes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, vinyl halide polymers andcopolymers, such as polyvinyl chloride, polyvinyl ethers, such aspolyvinyl methyl ether, polyvinylidene halides, such as polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics,such as polystyrene, polyvinyl esters, such as polyvinyl acetate,copolymers of vinyl monomers with each other and olefins, such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. poly(ethylene oxide-co-lactic acid)(PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,phosphoryl choline containing polymer, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as 2-hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,methacrylate polymers containing 2-methacryloyloxyethylphosphorylcholine(MPC) and n-vinyl pyrrolidone (VP), carboxylic acid bearing monomerssuch as methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),molecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, dextran, dextrin, hyaluronic acid, fragments andderivatives of hyaluronic acid, heparin, fragments and derivatives ofheparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide,elastin, elastin protein mimetics, or combinations thereof. Someexamples of elastin protein mimetics include (LGGVG)_(n), (VPGVG)_(n),Val-Pro-Gly-Val-Gly, or synthetic biomimeticpoly(L-glytanmate)-b-poly(2-acryloyloxyethyllactoside)-b-poly(1-glutamate)triblock copolymer. Note, the term “mimetic” can be used interchangeablywith the term “mimic.”

In some embodiments, the polymer can be poly(ethylene-co-vinyl alcohol),poly(methoxyethyl methacrylate), poly(dihydroxylpropyl methacrylate),polymethacrylamide, aliphatic polyurethane, aromatic polyurethane,nitrocellulose, poly(ester amide benzyl),co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]_(0.75)-[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (PEA-Bz),co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]_(0.75)-[N,N′-sebacoyl-L-lysine-4-amino-TEMPO amide]_(0.25)}(PEA-TEMPO), aliphatic polyester, aromatic polyester, fluorinatedpolymers such as poly(vinylidene fluoride-co-hexafluoropropylene),poly(vinylidene fluoride) (PVDF), and Teflon™ (polytetrafluoroethylene),a biopolymer such as elastin mimetic protein polymer, star orhyper-branched SIBS (styrene-block-isobutylene-block-styrene), orcombinations thereof. In some embodiments, where the polymer is acopolymer, it can be a block copolymer that can be, e.g., di-, tri-,tetra-, or oligo-block copolymers or a random copolymer. In someembodiments, the polymer can also be branched polymers such as starpolymers.

In some embodiments, a coating having the features described herein canexclude any one of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

Bioactive Agents

Bioactive agents that can form a conjugation with the acrylamide-basedcopolymer described herein can include one or more bioactive agent(s),which can be therapeutic, prophylactic, or diagnostic agent(s). Theseagents can have anti-proliferative or anti-inflammatory properties orcan have other properties such as antineoplastic, antiplatelet,anti-coagulant, anti-fibrin, antithrombogenic, antimitotic, antibiotic,antiallergic, antifibrotic, and antioxidant. The agents can becystostatic agents, agents that promote the healing of the endotheliumsuch as NO releasing or generating agents, agents that attractendothelial progenitor cells, agents that promote the attachment,migration or proliferation of endothelial cells (e.g., natriureticpeptides such as CNP, ANP or BNP peptide or an RGD or cRGD peptide),while impeding smooth muscle cell proliferation. Examples of suitabletherapeutic and prophylactic agents include synthetic inorganic andorganic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Some other examplesof the bioactive agent include antibodies, receptor ligands, enzymes,adhesion peptides, blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator, antigensfor immunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides, small interfering RNA (siRNA), small hairpinRNA (shRNA), aptamers, ribozymes and retroviral vectors for use in genetherapy. Examples of anti-proliferative agents include rapamycin and itsfunctional or structural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin(everolimus), and its functional or structural derivatives, paclitaxeland its functional and structural derivatives, as well as halofuginonewhich also has anti-fibrotic activity. Examples of rapamycin derivativesinclude 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, mometasone, or combinations thereof. Examplesof cytostatic substances include angiopeptin, angiotensin convertingenzyme inhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which can beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, bioactive RGD, SIKVAV peptides, elevating agents such ascANP or cGMP peptides, and genetically engineered endothelial cells. Theforegoing substances can also be used in the form of prodrugs orco-drugs thereof. The foregoing substances also include metabolitesthereof and/or prodrugs of the metabolites. The foregoing substances arelisted by way of example and are not meant to be limiting. Other activeagents which are currently available or that may be developed in thefuture are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than non-therapeuticlevels. The dosage or concentration of the bioactive agent can dependupon factors such as the particular circumstances of the patient, thenature of the trauma, the nature of the therapy desired, the time overwhich the administered ingredient resides at the vascular site, and ifother active agents are employed, the nature and type of the substanceor combination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

Examples of Implantable Device

As used herein, an implantable device can be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),heart valve prostheses, cerebrospinal fluid shunts, electrodes,pacemaker electrodes, catheters, sensors, endocardial leads (e.g.,FINELINE and ENDOTAK, available from Guidant Corporation, Santa Clara,Calif.), anastomotic devices and connectors, orthopedic implants such asscrews, spinal implants, and electro-stimulatory devices. The underlyingstructure of the device can be of virtually any design. The device canbe made of a metallic material or an alloy such as, but not limited to,cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP2ON,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP2ON” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers or bioabsorbable metals such asmagnesium could also be used with the embodiments of the presentinvention. In some embodiments, the device is a bioabsorbable stent.

Method of Use

In accordance with embodiments of the invention, an implantable devicehaving a coating that includes the acrylamide-based copolymer describedherein can be used for treating, preventing or ameliorating a medicalcondition. Preferably, the implantable device is a stent. The stentdescribed herein is useful for a variety of medical procedures,including, by way of example, treatment of obstructions caused by tumorsin bile ducts, esophagus, trachea/bronchi and other biologicalpassageways. A stent having the above-described coating is particularlyuseful for treating diseased regions of blood vessels caused by lipiddeposition, monocyte or macrophage infiltration, or dysfunctionalendothelium or a combination thereof, or occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents can be placedin a wide array of blood vessels, both arteries and veins. In someembodiments, the device described herein can be in dialysis, as grafts,or fistulae.

Representative examples of sites include the iliac, renal, carotid andcoronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described features can then beexpanded at the desired area of treatment. A post-insertion angiogramcan also be utilized to confirm appropriate positioning.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. An implantable device comprising a coating, thecoating comprising a conjugate of: a bioactive agent; a linkercomprising poly(ethylene glycol) (PEG), poly(alkylene oxide), C1-C12alkyl, C3-C12 cycloalkyl, C3-12 aryl, a peptide, a peptide sequence, aprotein, an oligomer of amino acids, succinic anhydride, glutaricanhydride, dimethyl succinic anhydride, methyl glutaric anhydride, athioester, a disulfide bond, a polylactic acid oligomer, apoly(lactic-co-glycolic acid) oligomer, Polycaprolactone oligomer, anester linkage, or an anhydride linkage; and a copolymer of Formula II:

wherein R₅ and R₆ are independently CH₃ or H; wherein R₇ is a straightor branched C₁-C₁₂ alkyl, aryl, cycloalkyl, or heterocyclic group;wherein n and m are independently mole ratios from about 0.01 to about0.99, with a proviso that n+m=1; and wherein the linker conjugates thebioactive agent to the copolymer.
 2. The implantable device of claim 1,wherein the linker comprises succinic anhydride, glutaric anhydride,dimethyl succinic anhydride, methyl glutaric anhydride, a thioester, adisulfide bond, a polylactic acid oligomer, a poly(lactic-co-glycolicacid) oligomer, a Polycaprolactone oligomer, an ester linkage, or ananhydride linkage.
 3. The implantable device of claim 1, wherein thelinker comprises succinic anhydride, glutaric anhydride, dimethylsuccinic anhydride, or methyl glutaric anhydride.
 4. The implantabledevice of claim 1, wherein the linker comprises poly(ethylene glycol)(PEG), a C1-C12 alkyl chain, or a peptide sequence.
 5. The implantabledevice of claim 4, wherein the peptide sequence comprisesglycine-phenylalinine-leucine-glycine.
 6. The implantable device ofclaim 1, wherein the linker comprises poly(ethylene glycol) (PEG),poly(alkylene oxide), C1-C12 alkyl, C3-C12 cycloalkyl, or C3-C12 aryl.7. The implantable device of claim 1, wherein the copolymer ispoly[N-(2-hydroxypropyl)methacrylamide-co-methoxyethyl methacrylate](HPMA-co-MOEMA).
 8. The implantable device of claim 1, wherein thecopolymer is a random or block copolymer.
 9. The implantable device ofclaim 1, which is a stent.
 10. The implantable device of claim 1,wherein the bioactive agent is selected from the group consisting ofhalofuginone, paclitaxel, docetaxel, estradiol, 17-beta-estradiol, anitric oxide donor, super oxide dismutase, a super oxide dismutasemimic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, a rapamycin derivative,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or aprodrug, co-drug, or combination of these.
 11. The implantable device ofclaim 9, wherein the bioactive agent is selected from the groupconsisting of halofuginone, paclitaxel, docetaxel, estradiol,17-beta-estradiol, a nitric oxide donor, super oxide dismutase, a superoxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, a rapamycinderivative, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, or aprodrug, co-drug, or combination of these.
 12. The implantable device ofclaim 1, wherein the coating comprises a layer of matrix comprising thecopolymer, linker and the bioactive agent.
 13. The implantable device ofclaim 1, wherein the coating comprises a topcoat comprising thecopolymer, linker and the bioactive agent.
 14. The implantable device ofclaim 1, wherein the coating further comprises one or more biocompatiblepolymers selected from the group consisting of poly(ester amide),polyhydroxyalkanoates (PHA), poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(tyrosine carbonates),poly(tyrosine ester), polyphosphoester, polyphosphoester urethane,polycyanoacrylates, poly(iminocarbonate), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, polyvinyl chloride,polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides,polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl esters,ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, polyamides, polycaprolactam, polycarbonates, polyimides,poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butylmethacrylate), poly(sec-butyl methacrylate), poly(isobutylmethacrylate), poly(tert-butyl methacrylate), poly(n-propylmethacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate),poly(methyl methacrylate), polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, poly(propylene oxide), poly(aspirin),2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,alkoxyacrylate, 3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), polypropyleneoxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxyfunctional poly(vinyl pyrrolidone), fibrin, fibrinogen, cellulose,starch, collagen, dextran, dextrin, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, and alginate.
 15. The implantable device of claim 14, whereinthe one or more biocompatible polymers are selected from the groupconsisting of poly(3-hydroxyalkanoates), poly(4-hydroxyalkanaotes),vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidenehalides, polyvinyl ketones, polyvinyl aromatics, polyamides andpolyvinyl esters.
 16. The implantable device of claim 14, wherein theone or more biocompatible polymers are selected from the groupconsisting of poly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate),poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA),hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEGacrylate (PEGA), PEG-methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone (VP),polyvinyl chloride, polyvinyl methyl ether, polyvinylidene chloride,polyacrylonitrile, polystyrene, polycaprolactam and polyvinyl acetate.17. A method of treating or ameliorating a medical condition, comprisingimplanting into a blood vessel the implantable device of claim
 9. 18. Amethod of forming a coating on an implantable device, comprising:providing a copolymer of Formula II:

providing a bioactive agent; providing a linker; conjugating thebioactive agent to the copolymer with the linker; and forming a coatingcomprising the conjugate on the implantable device; wherein R₅ and R₆are independently CH₃ or H; wherein R₇ is a straight or branched C₁-C₁₂alkyl, aryl, cycloalkyl, or heterocyclic group; wherein n and m areindependently mole ratios from about 0.01 to about 0.99, with a provisothat n+m=1; and wherein the linker comprises poly(ethylene glycol)(PEG), poly(alkylene oxide), C1-C12 alkyl, C3-C12 cycloalkyl, C3-C12aryl, a peptide, a protein, an oligomer of amino acids, succinicanhydride, glutaric anhydride, dimethyl succinic anhydride, methylglutaric anhydride, a thioester, a disulfide bond, a polylactic acidoligomer, a poly(lactic-co-glycolic acid) oligomer, a Polycaprolactoneoligomer, an ester linkage, or an anhydride linkage.
 19. The method ofclaim 18, wherein the linker comprises succinic anhydride, glutaricanhydride, dimethyl succinic anhydride, methyl glutaric anhydride, athioester, a disulfide bond, a polylactic acid oligomer, apoly(lactic-co-glycolic acid) oligomer, a Polycaprolactone oligomer, anester linkage, or an anhydride linkage.
 20. The method of claim 18,wherein the linker comprises succinic anhydride, glutaric anhydride,dimethyl succinic anhydride, or methyl glutaric anhydride.
 21. Themethod of claim 18, wherein the linker comprises poly(ethylene glycol)(PEG), an alkyl chain, or a peptide sequence.
 22. The method of claim21, wherein the peptide sequence comprisesglycine-phenylalinine-leucine-glycine.
 23. The method of claim 18,wherein the linker comprises poly(ethylene glycol) (PEG), poly(alkyleneoxide), C1-C12 alkyl, C3-C12 cycloalkyl, or C3-C12 aryl.
 24. The methodof claim 18, wherein the coating further comprises one or morebiocompatible polymers selected from the group consisting of poly(esteramide), polyhydroxyalkanoates (PHA), poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(tyrosine carbonates),poly(tyrosine ester), polyphosphoester, polyphosphoester urethane,polycyanoacrylates, poly(iminocarbonate), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, polyvinyl chloride,polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides,polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl esters,ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, polyamides, polycaprolactam, polycarbonates, polyimides,poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butylmethacrylate), poly(sec-butyl methacrylate), poly(isobutylmethacrylate), poly(tert-butyl methacrylate), poly(n-propylmethacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate),poly(methyl methacrylate), polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, poly(propylene oxide), poly(aspirin),2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,alkoxyacrylate, 3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), polypropyleneoxide-co-polyethylene glycol, poly(tetramethylene glycol), hydroxyfunctional poly(vinyl pyrrolidone), fibrin, fibrinogen, cellulose,starch, collagen, dextran, dextrin, fragments and derivatives ofhyaluronic acid, heparin, fragments and derivatives of heparin,glycosamino glycan (GAG), GAG derivatives, polysaccharide, elastin,chitosan, and alginate.
 25. The method of claim 24, wherein the one ormore biocompatible polymers are selected from the group consisting ofpoly(3-hydroxyalkanoates), poly(4-hydroxyalkanaotes), vinyl halidepolymers and copolymers, polyvinyl ethers, polyvinylidene halides,polyvinyl ketones, polyvinyl aromatics, polyamides and polyvinyl esters.26. The method of claim 24, wherein the one or more biocompatiblepolymers are selected from the group consisting ofpoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate), poly(3-hydroxyoctanoate),poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate), hydroxyethyl methacrylate (HEMA),hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEGacrylate (PEGA), PEG-methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC), n-vinyl pyrrolidone (VP),polyvinyl chloride, polyvinyl methyl ether, polyvinylidene chloride,polyacrylonitrile, polystyrene, polycaprolactam and polyvinyl acetate.